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TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass¹

Kristen Page^2,*,, Kristin M. Lierl^*, Valerie S. Hughes^*, Ping Zhou^*, John R. Ledford^* and Marsha Wills-Karp^,

^* Division of Critical Care Medicine and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation and Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229

It is becoming increasingly clear that innate immune mediators play a role in regulating adaptive immune responses in asthma pathogenesis. Cockroach exposure is a major risk factor for the development of asthma. In this study we asked whether German cockroach (GC) feces (frass) could initiate an innate immune response. Naive BALB/c mice were challenged with a single intratracheal inhalation of GC frass. Proinflammatory cytokines were significantly increased in the bronchoalveolar lavage fluid at 3 h and were maintained at higher than baseline levels for at least 24 h. Neutrophil migration into the airways was evident as early as 3 h but was maximal between 6 and 24 h postinhalation. The early increase in cytokine expression was independent of TLR2 or TLR4. Newly infiltrated airway neutrophils were responsible for maintaining high levels of cytokines in the airways. Using neutrophils as an early marker of the innate immune response, we show that show that neutrophils isolated from the airways following GC frass inhalation express TLR2 and release cytokines. GC frass directly affected neutrophil cytokine production via TLR2, but not TLR4, as evidenced by the use of TLR-neutralizing Abs and neutrophils from TLR-deficient mice. Activation of cytokine expression occurred via GC frass-induced NF-B translocation and DNA binding. These data show that GC frass contains a TLR2 agonist and, to our knowledge, this is the first report of an allergen directly activating cells of the innate immune system via TLR2 and suggests an important link between innate and adaptive immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant HL075568 (to K.P.) and HL67736 (to M.W.-K.).

² Address correspondence and reprint requests to Dr. Kristen Page, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML 7006, Cincinnati, OH 45229. E-mail address: kristen.page{at}cchmc.org

³ Abbreviations used in this paper: GC, German cockroach; BAL, bronchoalveolar lavage; MPO, myeloperoxidase; Pam₃CSK₄, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys₄-OH, 3HCl; PAMP, pathogen-associated molecular pattern.

This article has been cited by other articles:

				K. Page, J. R. Ledford, P. Zhou, and M. Wills-Karp A TLR2 Agonist in German Cockroach Frass Activates MMP-9 Release and Is Protective against Allergic Inflammation in Mice J. Immunol., September 1, 2009; 183(5): 3400 - 3408. [Abstract] [Full Text] [PDF]